Dietary supplement enhancing the muscular energy metabolism, comprising an alkanoyl carnitine and ribose

ABSTRACT

A health food/dietary supplement is disclosed suitable for enhancing muscular energy metabolism, comprising as its characterizing active ingredits an alkanoyl L-carnitine and ribose.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.10/048,590 filed Feb. 1, 2002 which in turn is a U.S. national phase ofPCT/IT01/00283 filed Jun. 1, 2001 claiming priority of Italianapplication RM2000A000323 filed Jun. 14, 2000.

BACKGROUND OF THE INVENTION

The present invention relates to a health food/dietary supplementcomprising as its characterising ingredients an alkanoyl L-carnitineselected from the group consisting of isovaleryl L-carnitine andpropionyl L-carnitine or their pharmacologically acceptable salts ormixtures of the same and a monosaccharide pentose, particularly riboseor its phosphorylated analogues.

It has been found that the above-mentioned composition is extremelyeffective in exerting a potent stimulation of muscular energymetabolism, and can thus be profitably used in the prevention ofmyocardial insufficiency and in post-infarct conditions, as well as inthe course of prolonged muscular effort during physical and sportingexercises, owing to the unexpected synergistic effect exerted by itscomponents.

Isovaleryl L-carnitine, a natural component of the pool of carnitines,presents specific activity at lysosomal level and on the cytosolicmovements of calcium. It is therefore capable of intervening inproteolytic processes such as occur during intense, prolonged effort andof protecting a number of organs, such as the liver, against the actionof toxic substances.

Propionyl L-carnitine exerts an intense antioxidant effect and isparticularly effective in enhancing the peripheral circulation andcardiac functional capacity.

Moreover, muscular carnitine transferase possesses a greater affinityfor propionyl L-carnitine than for L-carnitine, and consequentlypropionyl L-carnitine possesses a higher degree of specificity forcardiac and skeletal muscle. In addition, propionyl L-carnitinetransferase, transporting the propionyl group, increases the uptake ofthis component by the muscle cells, which may be of particularimportance for energy purposes, in that the propionate can be used bythe mitochondria as an anapleurotic substrate and provide energy in theabsence of oxygen.

Equally well known are the metabolic efects of ribose. Ribose is amonosaccharide pentose which is important in the body for the synthesisof nucleotides and other metabolic products. It is formed by conversionof glucose via the pentose phosphates. In the presence of a ribokinaseribose is phosphorylated to ribose-5-phosphate which, through theproduction of 5-phosphoribosyl-1-pyrophosphate (PRPP), can be used forthe synthesis of nucleotides necessary for the production of ATP. PRPP,in addition to intervening in the production of ATP, is also importantfor the synthesis of nucleotides such as adenine and hypoxanthine and ofribonucleotides and deoxyribonucleotides.

It has now been found surprisingly that a composition comprising acombination of the following as its characterising components:

(a) an alkanoyl L-carnitine selected from the group comprisingisovaleryl L-carnitine, propionyl L-carnitine or their pharmacologicallyacceptable salts or mixtures of the same; and

(b) ribose or one of its phosphorylated derivatives thereof,

constitutes an effective health food/dietary supplement for theprevention of states of myocardial or skeletal muscle dysfuntion relatedto conditions of anoxia or insufficient energy supply as occurring incoronary or post-infarct disorders or during prolonged physical activityand muscle fatigue, owing to the potent and unexpected synergisticeffect exerted by its components.

The weight-to-weight ratios of the above-mentioned components (a):(b)range from 1:1 to 1:10.

The dietary supplement according to the present invention mayadditionally contain

(c) a “carnitine” selected from the group comprising L-carnitine, acetylL-carnitine, butyryl L-carnitine and valeryl L-carnitine, or theirpharmacologically acceptable salts or mixtures of the same.

The weight-to-weight ratios of the above-mentioned components(a):(b):(c) range from 1:1:1 to 1:10:2.

The surprising synergistic effect achieved with the combination of“carnitines” (term denoting collectively both L-carnitine and thealkanoyl L-carnitines), particularly isovaleryl L-carnitine and/orpropionyl L-carnitine, and ribose, has been demonstrated by severalpharmacological tests (some of which are described here below) chosen insuch a way as to prove strongly predictive for the purposes of thepractical use of this composition in the preventive/nutritional/dieteticfield.

In particular, this unexpected synergistic effect on the increase inenergy capabilities at both cardiac and muscular level exerted by thecombination according to the present invention enables it to be used inthe prevention of both myocardial insufficiency and of muscle fatiguesuch as occur in cases of myocardial ischaemia or in the course ofintense muscular effort due to prolonged physical exercise or sportingactivity.

DETAILED DESCRIPTION OF THE INVENTION

Test of ATP Concentrations in Heart Subjected to Anoxia

In this test the technique adopted was the one using papillary muscle ofrabbit heart perfused and subjected to anoxia which, as is known, leadsto an impoverishment of its ATP energy reserves. With this test, the aimwas to observe whether or not preventive treatment with isovalerylL-carnitine, with propionyl L-carnitine, with a carnitine combination orwith ribose, or with a combination of these was capable of protectingcardiac muscle against the loss of ATP induced by anoxia.

In this test, a batch of New Zealand rabbits was used, subdivided intodifferent groups which were injected intravenously every day for threeconsecutive days with isovaleryl L-carnitine alone (100 mg/kg),propionyl L-carnitine alone (100 mg/kg) or a carnitine combinationconsisting of propionyl L-carnitine (25 mg/kg), acetyl L-carnitine (25mg/kg), L-carnitine (25 mg/kg), and isovaleryl L-carnitine (25 mg/kg) orwith ribose alone (100 mg/kg), or ribose combined with theabove-mentioned “carnitines”.

At the end of the third day of treatment, all the animals weresacrificed and their hearts excised. Sections of papillary musclemeasuring 1 mm in diameter and 4-5 mm in thickness were isolated fromthe excised hearts. The isolated papillary muscle was perfused in athermostatic bath with a saturated 100% O₂ solution.

The anoxic state was obtained by introducing 100% N₂ instead of O₂ intothe bath. For the measurement of the ATP concentrations in thepapaillary muscle the method described by Strehler was adopted (StrehlerB. L. Methods in Enzymology 111 N.Y. Acad. Press., 879, 1957).

The analysis was carried out on tissue samples maintained in conditionsof perfusion with oxygen for 90 minutes and after a period of anoxia ofthe same duration.

The results of this test, presented in Table 1, indicate that propionylL-carnitine, isovaleryl L-carnitine, the carnitine combination andribose are individually capable of partly protecting the ATP present inpapillary muscle against anoxia, but that it was only with thecombination of propionyl L-carnitine or isovaleryl L-carnitine plusribose or with the combination of the carnitine combination plus ribosethat complete protection agaisnt the anoxia-induced reduction in ATPcould be obtained, thus demonstrating the potent synergistic effectexerted by the components of the combination. TABLE 1 Test of ATPconcentrations in papillary muscle of heart subjected to hynoxia ATPconcentration (mol/g tissue) Treatment Before hypoxia After hypoxiaControls 1.60 ± 0.55 0.41 ± 0.055 Isovaleryl L-carnitine 1.50 ± 0.600.55 ± 0.65  Propionyl L-carnitine 1.64 ± 0.79 0.60 ± 0.040 Carnitinecombination 1.55 ± 0.50 0.62 ± 0.060 Ribose 1.62 ± 0.39 0.55 ± 0.075Isovaleryl L-carnitine + ribose 1.50 ± 0.25 1.15 ± 0.055 PropionylL-carnitine + ribose 1.61 ± 0.45 1.25 ± 0.35  Carnitine combination +ribose 1.65 ± 0.60 1.16 ± 0.30 

Experimental Myocardial Anoxia Test

Adopting the technique described by Selych (Selych et al., Angiology,11, 398, 1960) and modified by Clark (Clark C., J. Pharmacol. Methods,3, 357, 1980), these tests were used to evaluate the protective activityof isovaleryl L-carnitine, propionyl L-carnitine, carnitine combination,ribose and various combinations of the same against ventriculararrhythmias induced by left coronary ligation in the rat.

Coronary occlusion and the resulting myocardial anoxia lead, after 5-8minutes, to the onset of arrhythmias. In these tests, ventricularectopic contractions were counted for a period of 30 minutes afterligation both in control rats and in rats that had received slowinjections into the left ventricle, 15 minutes before ligation, of asolution containing isovaleryl L-carnitine alone (100 mg/kg), propionylL-carnitine alone (100 mg/kg), or carnitine combination alone consistingof propionyl L-carnitne (25 mg/kg), acetyl L-carnitine (25 mg/kg) andisovaleryl L-carnitine (25 mg/kg) or ribose alone (100 mg/kg), or acombination of ribose plus isovaleryl L-carnitine or propionylL-carnitine or a combination of ribose plus carnitine combination at thedoses described above.

The results of this test (Table 2) indicate that, whereas isovalerylL-carnitine alone or propionyl L-carnitine alone or carnitinecombination alone or ribose alone produce only slight reductions in thenumber of ectopic contractions compared to controls, such contractionsare reduced almost to the extent of disappearing altogether when riboseis injected in combination with isovaleryl L-carnitine, or propionylL-carnitine, or carnitine combination, thus demonstrating the potent andunexpected synergistic effect exerted by the combination according tothe present invention. TABLE 2 Test of arrhythmia induced by myocardialanoxia N. of ectopic Start of contractions arrhythmias during 30 minutesTreatment after (mins) after ligation Controls 5-7 989 ± 96 IsovalerylL-carnitine 5-7 860 ± 75 Propionyl L-carnitine 5-8 830 ± 86 Carnitinecombination 5-8 810 ± 99 Ribose 5-7  855 ± 110 Isovaleryl L-carnitine +ribose 6-7 270 ± 95 Propionyl L-carnitine + ribose 6-8  230 ± 112Carnitine combination + ribose 6-8 207 ± 93

Some non-limiting examples of compositions according to the presentinvention are given hereinbelow: Lozenges, Capsules, Tablets 1)Propionyl L-carnitine 500 mg Ribose 500 mg 2) Isovaleryl L-carnitine 500mg Ribose 500 mg 3) Propionyl L-carnitine 125 mg Acetyl L-carnitine 125mg L-carnitine 125 mg Isovaleryl L-carnitine 125 mg Ribose 500 mgGranulates or vials 4) Propionyl L-carnitine 1 g Ribose 1 g 5)Isovaleryl L-carnitine 1 g Ribose 1 g 6) Propionyl L-carnitine 1 gRibose 2.5 g 7) Propionyl L-carnitine 250 mg Acetyl L-carnitine 250 mgIsovaleryl L-carnitine 250 mg L-carnitine 250 mg Ribose 2.5 g 8)Propionyl L-carnitine 250 mg Acetyl L-carnitine 250 mg IsovalerylL-carnitine 250 mg L-carnitine 250 mg Ribose 2 g Ribonucleic acid 100 mgDeoxyribonucleic acid 100 mg 9) Propionyl L-carnitine 250 mg AcetylL-carnitine 250 mg Isovaleryl L-carnitine 250 mg L-carnitine 250 mgRibose 2 g L-glutamine 100 mg L-alanine 100 mg L-arginine 100 mgL-glicine 100 mg L-histidine 100 mg L-isoleucine 100 mg L-phenylalanine50 mg L-threonine 50 mg L-serine 100 mg 10) Propionyl L-carnitine 250 mgAcetyl L-carnitine 250 mg Isovaleryl L-carnitine 250 mg L-carnitine 250mg Ribose 1 g Destrose 0.5 g Fructose 0.5 g Maltose 0.5 g 11) PropionylL-carnitine 250 mg Acetyl L-carnitine 250 mg Isovaleryl L-carnitine 250mg L-carnitine 250 mg Ribose 1 g Glucose-1,6-diphosphate 200 mgFructose-1,6-diphosphate 200 mg Galactose-1,6-phosphate 200 mgGlycerol-3-phosphate 200 mg Phosphenylpyruvate 100 mg Thiaminepyrophosphate 5 mg Pyridoxal-5-phosphate 5 mg Magnesium stearate 2 mg12) Propionyl L-carnitine 250 mg Acetil L-carnitine 250 mg IsovalerylL-carnitine 250 mg L-carnitine 250 mg Ribose 1 g Vit. A 1250 U.I. Vit.B₁ 0.5 mg Vit. B₆ 30 mg Vit. C 50 mg Vit. E 5 mg Nicotinammide 25 mgVit. B₁₂ 100 mcg Vit. D 100 U.I. Pantothenic acid 30 mg Magnesiumglycinate 5 mg Manganese 1 mg L-Selenomethionine 50 mcg Molybdenum 10mcg Zinc 1 mg

What is meant by a pharmacologically acceptable salt of the variouscarnitines mentioned in the present invention, is, in addition to therespective inner salts, any salt of these with an acid which does notgive rise to unwanted toxic or side effects. These acids are well knownto pharmacologists and to experts in pharmaceutical technology.

Non-limiting examples of such salts are the following: chloride;bromide; iodide; aspartate, acid aspartate; citrate, acid citrate;tartrate; phosphate, acid phosphate; fumarate, acid fumarate;glycerophosphate; glucose phosphate; lactate; maleate, acid maleate;mucate; orotate; oxalate, acid oxalate; sulphate, acid sulphate;trichloroacetate; trifluoroacetate and methane sulphonate.

Among these salts, isovaleryl L-carnitine acid fumarate (U.S. Pat. No.5,227,518) is particularly preferred.

A list of FDA-approved pharmacologically acceptable acids is given inInt. J. Pharm., 33, 1986, 201-217, the latter publication beingincorporated in the present specification by reference.

The supplement of the invention may further comprise vitamins,coenzymes, mineral substances, aminoacids and antioxidants. Thesupplement may be manufactured in the form of tablets, lozenges,capsules, pills, granulates, syrups, vials or drops.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

1. A food/dietary supplement in the form of tablets, capsules, lozenges,pills, granulates, creams, syrups or drops which comprises the followingcharacterizing ingredients: (a) an alkanoyl L-carnitine selected fromthe group consisting of isovaleryl L-carnitine, and propionylL-carnitine or the pharmacologically acceptable salts thereof ormixtures thereof; and (b) ribose or a phosphorylate derivative thereofwherein the weight ratio of ingredients (a):(b) ranges from 1:1 to 1:10.2. The supplement of claim 1 which further comprises vitamins, sugars,coenzymes, mineral substances, aminoacids, peptides and antioxidants. 3.The supplement of claim 2 wherein the pharmacologically acceptable saltis selected from the group consisting of chloride; bromide; iodide;aspartate, acid aspartate; citrate, acid citrate; tartrate; phosphate,acid phosphate; fumarate, acid fumarate; glycerophosphate; glucosephosphate; lactate; maleate, acid maleate; mucate; orotate; oxalate;acid oxalate; sulphate, acid sulphate; trichloroacetate;trifluoroacetate and methane sulphonate.
 4. A food/dietary supplement inthe form of tablets, capsules, lozenges, pills, granulates, creams,syrups or drops which comprises the following characterizingingredients: (a) an alkanoyl L-carnitine selected from the groupconsisting of isovaleryl L-carnitine, and propionyl L-carnitine or thepharmacologically acceptable salts thereof or mixtures thereof; (b)ribose or a phosphorylate derivative thereof, and (c) a carnitineselected from the group comprising L-carnitine, acetyl L-carnitine,butyryl L-carnitine and valeryl L-carnitine or the pharmacologicallyacceptable salts or mixtures thereof; wherein the weight ratio ofingredients (a):(b):(c) ranges from 1:1 to 1:10:2.
 5. The supplement ofclaim 4 which further comprises vitamins, sugars, coenzymes, mineralsubstances, aminoacids, peptides and antioxidants.
 6. The supplement ofclaim 4 wherein the pharmacologically acceptable salt is selected fromthe group consisting of chloride; bromide; iodide; aspartate, acidaspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate;fumarate, acid fumarate; glycerophosphate; glucose phosphate; lactate;maleate, acid maleate; mucate; orotate; oxalate; acid oxalate; sulphate,acid sulphate; trichloroacetate; trifluoroacetate and methanesulphonate.
 7. The supplement of claim 4, in unit dosage form,comprising: Propionyl L-carnitine 125 mg Acetyl L-carnitine 125 mgL-carnitine 125 mg Isovaleryl L-carnitine 125 mg Ribose 500 mg


8. The supplement of claim 4, in unit dosage form, comprising: PropionylL-carnitine 250 mg Acetyl L-carnitine 250 mg Isovaleryl L-carnitine 250mg L-carnitine 250 mg Ribose 2 g Ribonucleic acid 100 mgDeoxyribonucleic acid 100 mg


9. The supplement of claim 4, in unit dosage form, comprising: PropionylL-carnitine 250 mg Acetyl L-carnitine 250 mg Isovaleryl L-carnitine 250mg L-carnitine 250 mg Ribose 2 g L-glutamine 100 mg L-alanine 100 mgL-arginine 100 mg L-glicine 100 mg L-histidine 100 mg L-isoleucine 100mg L-phenylalanine 50 mg L-threonine 50 mg L-serine 100 mg


10. The supplement of claim 4, in unit dosage form, comprising:Propionyl L-carnitine 250 mg Acetyl L-carnitine 250 mg IsovalerylL-carnitine 250 mg L-carnitine 250 mg Ribose 1 g Glucose-1,6-diphosphate200 mg Fructose-1,6-diphosphate 200 mg Galactose-1,6-phosphate 200 mgGlycerol-3-phosphate 200 mg Phosphenylpyruvate 100 mg Thiaminepyrophosphate 5 mg Pyridoxal-5-phosphate 5 mg Magnesium stearate 2 mg


11. The supplement of claim 4, in unit dosage form, comprising:Propionyl L-carnitine 250 mg Acetil L-carnitine 250 mg IsovalerylL-carnitine 250 mg L-carnitine 250 mg Ribose 1 g Vit. A 1250 U.I. Vit.B₁ 0.5 mg Vit. B₆ 30 mg Vit. C 50 mg Vit. E 5 mg Nicotinamide 25 mg Vit.B₁₂ 100 mcg Vit. D 100 U.I. Pantothenic acid 30 mg Magnesium glycinate 5mg Manganese 1 mg L-Selenomethionine 50 mcg Molybdenum 10 mcg Zinc 1 mg


12. A method for the treatment of states of myocardial or skeletalmuscle anoxia occurring in coronary or post-infarct disorders or duringprolonged physical activity and muscle fatigue, which comprisesadministering to an individual in need thereof a combination compositioncomprising the following ingredients: (a) an alkanoyl L-carnitineselected from the group consisting of isovaleryl L-carnitine, propionylL-carnitine or the pharmacologically acceptable salts thereof ormixtures thereof, and (b) ribose or a phosphorylate derivative thereof.13. A method for the treatment of states of myocardial or skeletalmuscle dysfunction related to conditions of anoxia or insufficientenergy supply as occurring in coronary or post-infarct disorders orduring prolonged physical activity and muscle fatigue, which comprisesadministering to an individual in need thereof a combination compositioncomprising the following ingredients: (a) an alkanoyl L-carnitineselected from the group consisting of isovaleryl L-carnitine, propionylL-carnitine or the pharmacologically acceptable salts thereof ormixtures thereof, and (b) ribose or a phosphorylate derivative thereof.14. A method for the treatment of states of myocardial or skeletalmuscle anoxia occurring in coronary or post-infarct disorders or duringprolonged physical activity and muscle fatigue, which comprisesadministering to an individual in need thereof a combination compositioncomprising the following ingredients: (a) an alkanoyl L-carnitineselected from the group consisting of isovaleryl L-carnitine, propionylL-carnitine or the pharmacologically acceptable salts thereof ormixtures thereof, (b) ribose or a phosphorylate derivative thereof, and(c) a carnitine selected from the group comprising L-carnitine, acetylL-carnitine, butyryl L-carnitine and valeryl L-carnitine or thepharmacologically acceptable salts or mixtures thereof.
 15. A method forthe treatment of states of myocardial or skeletal muscle dysfunctionrelated to conditions of anoxia or insufficient energy supply asoccurring in coronary or post-infarct disorders or during prolongedphysical activity and muscle fatigue, which comprises administering toan individual in need thereof a combination composition comprising thefollowing ingredients: (a) an alkanoyl L-carnitine selected from thegroup consisting of isovaleryl L-carnitine, propionyl L-carnitine or thepharmacologically acceptable salts thereof or mixtures thereof, (b)ribose or a phosphorylate derivative thereof, and (c) a carnitineselected from the group comprising L-carnitine, acetyl L-carnitine,butyryl L-carnitine and valeryl L-carnitine or the pharmacologicallyacceptable salts or mixtures thereof.